The main objective of this work is to develop a new technique for delivering antitumor drugs to specified target tissues in order to reduce drug toxicity to normal, nontarget tissues. Our approach involves drug carriers made of phospholipids, called liposomes. The current project has two specific aims: (1) to develop the delivery of antitumor drugs to specific target tissues by using liposomes with different physical and chemical properties, and (2) to define and solve possible problems before use of this drug delivery system for clinical applications. One of the major barriers to using liposomes as carriers of antitumor drugs is their high uptake by organs rich in reticuloendothelial cells, particularly the liver. We have found that liposomes prepared with sialic acid or sialogangliosides have a low uptake in the liver, and that liposomes prepared with phosphatidylinositol or monogalactosyldiglyceride have an unusually high affinity to the spleen. The kinetics of intracellular release of liposome-encapulated 125IUdR show that about 50% and 85% of the total injected 125I-radioactivity was in the mouse liver nuclei at 30 and 60 minutes, respectively, after an i.v. injection of liposomes containing 125IUdR. Use of autoradiography and liposomes containing actinomycin D also showed that the drug was incorporated into Ehrlich ascites tumor cell nuclei. These findings indicate that antitumor drugs carried by liposomes are rapidly released within cells, and that the drug localizes in the nucleus, the specific site of action.